MEKanistic's MTX-531 Shows Promising Results in Preclinical Cancer Models

MEKanistic Therapeutics Inc., a biotechnology firm renowned for advancing next-generation kinase inhibitors for cancer therapy, has unveiled promising preclinical research on its primary drug candidate, MTX-531. Detailed in the esteemed journal Nature Cancer, MTX-531 is an experimental therapy designed to inhibit two crucial proteins, EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase), which are vital for cancer cell survival and growth.

Danny Cunagin, CEO of MEKanistic Therapeutics, expressed enthusiasm about the research findings. He emphasized the potential of MTX-531 to address the fundamental causes of resistance to current cancer treatments by targeting adaptive resistance mechanisms through a dual inhibition strategy. Such an approach aims to halt cancer progression more effectively than single-target treatments, with plans to advance the therapy into clinical trials.

Key Insights from the MTX-531 Research

Potency and Selectivity with Notable Tolerability

The preclinical studies highlighted MTX-531's nanomolar potency against both EGFR and PI3K, achieving 14.7 nM for EGFR and 6.44 nM for PI3K, with substantial selectivity demonstrated through broad kinome testing. Unlike other pan-PI3K inhibitors, MTX-531 did not induce hyperglycemia in mice at therapeutic doses. This is a significant departure from existing therapies, which often result in increased blood glucose and insulin levels in both preclinical and clinical settings.

Judith Sebolt-Leopold, PhD, Chief Scientific Officer at MEKanistic Therapeutics, noted that MTX-531 is the first PI3K inhibitor capable of selectively targeting both EGFR and PI3K without causing hyperglycemia. This unique feature, achieved through precise computational design, enhances its therapeutic index and resilience against adaptive resistance mechanisms often seen with prior PI3K inhibitors.

Efficacy as Monotherapy and in Combination

As a monotherapy, MTX-531 demonstrated notable tumor regression in preclinical models of head and neck squamous cell carcinoma (HNSCC). The oral therapy effectively inhibited PI3K and EGFR signaling, achieving objective responses across all HNSCC models tested. Complete tumor regressions and survival improvements were observed, with improvements ranging from 62% to over 500% across different models.

When combined with a MEK inhibitor (trametinib) or a KRAS inhibitor (sotorasib), MTX-531 significantly increased the incidence of tumor regressions, achieving a 100% objective response rate in various KRAS mutant colorectal (CRC) and pancreatic tumor models.

Dr. Sebolt-Leopold added that the preclinical data collectively show MTX-531's effectiveness in inhibiting tumor growth in cancers with PIK3CA and KRAS mutations, which are often associated with aggressive behavior and resistance to standard therapies. MTX-531 was well tolerated and outperformed combinations of drugs targeting EGFR and PI3K individually, showcasing its versatility and broader potential in treating difficult-to-treat cancers.

Development of MTX-531

Currently, investigational new drug-enabling toxicology studies sponsored by the National Cancer Institute's (NCI) Experimental Therapeutics (NExT) Program are underway. This program supports the advancement of promising new drug discovery and development projects. MEKanistic Therapeutics collaborates with NCI staff on a milestone-driven project team to evaluate the safety and efficacy of MTX-531 in cancer patients.

Christopher Whitehead, PhD, Co-founder and COO of MEKanistic Therapeutics, highlighted the partnership with NCI as a testament to MTX-531's promising potential. With NCI's support and the company's efforts in GMP manufacturing and drug product development, significant strides are being made toward bringing this innovative therapy closer to clinical trials and ultimately to patients in need.

About MEKanistic Therapeutics, Inc.

Based in Minneapolis, MN, MEKanistic Therapeutics Inc. is a privately held biotechnology company focused on developing innovative kinase inhibitors for cancer treatment. The company aims to design drugs that prevent tumors from developing resistance to targeted therapies by exploring the landscape of signal transduction pathways. Their lead candidate, MTX-531, is a single molecule designed to selectively block EGFR and PI3K pathways, crucial in promoting tumor progression.

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